In studies of the experimental pathology of tissue injury in myocardial infarction in dogs, we have shown an early loss of integrity of cell components. The membranes of myocardial cells fail as a barrier to ions and macromolecules with consequent swelling and functional disruption of cells and organelles, and lysosomes release into the cytosol, and surrounding tissue hydrolytic enzymes which may augment regional injury. The two processes appear interrelated and self-perpetuating since partially damaged cells may show injury to one or another compartment whereas cells in the area of necrosis always show injury to all compartments. Furthermore, the area of necrosis continues to expand for up to 18 hours after initiation of ischemia indicating that a mechanism exists for continued injury to tissues marginally perfused at the outset. Since lysosomal hydrolases are known to play an important role in tissue injury, we propose to study the role of lysosomes and lysosomal hydrolases in the augmentation of tissue injury in experimental myocardial infarction, and to study procedures which may protect the ischemic myocardial. This proposal is designed to test the following hypotheses: 1) that loss of integrity of myocardial cells and organelles is critical in the amplification of ischemic injury; 2) that hydrolytic enzymes released from lysosomes of myocardial cells damaged early in ischemia play a role in this amplification of tissue injury; and 3) that pharmacologic agents which affect tissue integrity can influence the development of necrosis. The techniques to be employed have been in use in our laboratories for a minimum of three years and include stable animal models for both short term and long term infarctions, as well as appropriate morphological, cytochemical and biochemical evaluations of the extent of injury. BIBLIOGRAPHIC REFERENCES: Roos, D., Goldstein, I.M., Kaplan, H.B., Weissmann, G., Dissociation of phagocytosis, metabolic stimulation and lysosomal enzyme release in human leukocytes. Agents and Actions 6:256-262, 1976. Weissmann, G., The pharmacological control of immunologically-induced inflammation In: Infection and Immunology in the Rheumatic Diseases (D.C. Dumonde, ed.) Bleckwell Scientific Publications, Oxford, pp. 503-510, 1976.